The long-term objective of this laboratory is to investigate the role of cytokines in the endogenous immune response to cancer, with the goal of exploiting these anti-tumor responses to characterize the prognosis of, and/or design innovative treatment for, human cancers. Interferon gamma (IFN-gamma) appears from prior data to be an important endogenous mediator of the anti-tumor response. The objective of this proposal is to further define the mechanisms of the direct anti-tumor effect of IFN- gamma with particular focus on the interferon regulatory factors 1 and 2 (IRF-1 and IRF-2). Specifically: (1) To characterize the consequences of IRF-1 expression in murine tumor cell lines, murine tumor culture models expressing transfected IRF-1 will be used, with measurement of tumor growth rate in vitro, MHC expression by FACS and RT-PCR analysis, and cell cycle control. (2) To characterize the consequences of IRF-2 expression in murine tumor cell lines, murine tumor culture models expressing transfected IRF-2 will be used, with measurement of growth rate, cell cycle control and sensitivity to exogenous cytokine effects in vitro. (3) To investigate the in vivo effects of IRF-1 or IRF-2 expression in terms of growth rate, tumor immunity, sensitivity to tumor necrosis factor - (TNF), endotoxin-(LPS), and IL-12-induced tumor regression, and the effects of host immune responses on the expression of IRF-1 and IRF-2, murine in vivo tumor models will be used. (4) The basal and inducible expression of hIRF-1 and hIRF-2 in human tumor cell lines, and the presence of IRF-1 and IRF-2 expression in archival human tumor specimens will be assessed and correlated with clinical behavior. These experiments will elucidate the roles of IRF-1 and IRF-2 in tumor growth in intact, immunocompetent animals, and begin to address the potential clinical importance of IRF expression in human tumors.